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Airway and Systemic Effects of Hydrofluoroalkane Formulations of High-Dose Ciclesonide and Fluticasone in Moderate Persistent Asthma^*

^* From the Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.

Correspondence to: Brian J. Lipworth, MD, Professor of Allergy and Respiratory Medicine, Asthma & Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; e-mail: b.j.lipworth{at}dundee.ac.uk

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: There are no data comparing the relative effects of high-dose ciclesonide (CIC) and fluticasone propionate (FP) on airway and systemic outcomes in patients with moderate persistent asthma.

Objective: We elected to evaluate the relative effects of CIC and FP on the plasma cortisol response to stimulation with human corticotropin-releasing factor (hCRF) and bronchial hyperresponsiveness to methacholine as the primary outcome variables, in addition to secondary outcomes of overnight 10-h urinary cortisol (OUC) levels, exhaled nitric oxide levels, lung function, symptoms, and quality of life.

Methods: Fourteen patients with moderate persistent asthma (mean FEV₁, 67% predicted [prior to each randomized treatment]) completed the study, which had a randomized, double-blind, double-dummy, crossover design, per protocol. Patients stopped receiving their usual inhaled corticosteroids for the duration of the study and instead began receiving salmeterol, 50 µg twice daily, and montelukast, 10 mg once daily, for the 2-week washout periods prior to each randomized treatment, in order to prevent dropouts after withdrawal from inhaled corticosteroid therapy. Patients received 4 weeks of either CIC, 200 µg ex-valve (160 µg ex-actuator) four puffs twice daily, plus FP-placebo, four puffs twice daily, or FP, 250 µg ex-valve (220 µg ex-actuator) four puffs twice daily, plus CIC-placebo, four puffs twice daily. Salmeterol and montelukast were withheld for 72 h prior to each postwashout baseline visit, and CIC or FP was withheld for 12 h prior to each posttreatment visit.

Results: FP, but not CIC, when compared to respective baseline values, significantly suppressed (p < 0.05) plasma cortisol levels as follows: FP prior to receiving hCRF: geometric mean fold difference, 1.2; 95% confidence interval (CI), 1.1 to 1.3; CIC prior to receiving hCRF: geometric mean fold difference, 0.9; 95% CI, 0.8 to 1.0; FP 30 min after receiving hCRF: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; CIC 30 min after receiving hCRF: geometric mean fold difference, 1.0; 95% CI, 0.9 to 1.2; OUC after FP administration: geometric mean fold difference, 1.9; 95% CI, 1.4 to 2.6; OUC after CIC administration: geometric mean fold difference, 1.2; 95% CI, 0.9 to 1.5. There was also a significantly lower (p < 0.05) mean value for OUC levels after FP administration than after CIC administration (geometric mean fold difference, 1.5; 95% CI, 1.1 to 2.0). Therapy with CIC and FP, compared to respective baselines, significantly increased (p < 0.05) the provocative concentration of methacholine causing a 20% fall in FEV₁, as follows: CIC: doubling dilution difference, 0.8; 95% CI, 0.1 to 1.6; FP: doubling dilution difference, 1.0; 95% CI, 0.1 to 2.0. It also significantly reduced (p < 0.05) exhaled nitric oxide levels, as follows: CIC: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; FP: geometric mean fold difference, 1.9; 95% CI, 1.3 to 2.8. There was no effect on other secondary efficacy outcomes.

Conclusion: FP, 2,000 µg daily, but not CIC, 1,600 µg daily, significantly suppressed hypothalamic-pituitary-adrenal axis outcomes, with OUC levels being lower after FP administration than after CIC administration. Both drugs significantly improved airway outcomes in terms of methacholine bronchial hyperresponsiveness and exhaled nitric oxide levels. The present results would therefore suggest that CIC might confer a better therapeutic ratio than FP when used at higher doses.

Key Words: asthma • ciclesonide • exhaled nitric oxide • fluticasone propionate • human corticotropin-releasing factor • methacholine bronchial challenge • Mini-Asthma Quality-of-Life Questionnaire • overnight 10-h urinary cortisol

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Ciclesonide (CIC) is a topically active, potent inhaled corticosteroid that is currently undergoing the late stages of clinical development. It is a prodrug, which is converted on site by esterase activity in the lung to its active metabolite, desisobutyryl-CIC. The extrafine hydrofluoroalkane solution formulation of CIC produces 50% respirable dose delivery and high pulmonary bioavailability for the active moiety. However, the active moiety has 99% plasma protein binding, resulting in a very low concentration of free unbound desisobutyryl-CIC being present in the systemic circulation, which, along with almost complete hepatic first-pass metabolism for the swallowed fraction and rapid clearance, produce a favorable systemic safety profile. This has been borne out by preliminary data showing no significant hypothalamic-pituitary-adrenal (HPA) axis suppression with CIC at a daily dose of up to 1,600 µg, on a variety of end points, including 24-h integrated plasma and urine cortisol profiles, as well as the dynamic adrenocorticotropic hormone-stimulated cortisol response.¹²³⁴ Another sensitive method of dynamic stimulation testing is the 100-µg bolus human corticotropin-releasing factor (hCRF) stimulation test.⁵ This has been shown to be as sensitive as the insulin stress test for detecting impaired adrenal reserves in corticosteroid-treated patients.⁶

In order to evaluate the therapeutic ratio, it is also important to consider the effects on sensitive airway efficacy outcomes, such as bronchial hyperresponsiveness. In this respect, bronchial hyperresponsiveness to methacholine is more closely related to asthmatic inflammation than to lung function, when assessing the response to inhaled corticosteroids.⁷⁸ We have previously shown that hydrofluoroalkane formulations of CIC, 400 µg daily, and fluticasone propionate (FP), 500 µg daily for 4 weeks, exhibit equivalent efficacy on bronchial hyperresponsiveness to methacholine challenge in patients with mild-to-moderate asthma.⁹

The purpose of the present study was to evaluate the relative airway and systemic effects of hydrofluoroalkane formulations of CIC, 200 µg four puffs twice daily, and FP, 250 µg four puffs twice daily, on hCRF cortisol response and on methacholine bronchial hyperresponsiveness (the primary systemic and airway outcomes, respectively) in patients with moderate, persistent asthma, in order to ascertain the relative therapeutic ratio of these two drugs.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
Eligible patients were nonsmokers with moderate, persistent asthma¹⁰¹¹ who had been stable for at least 3 months prior to the study and had not received a course of oral corticosteroids or antibiotics during this period. Patients were required to be receiving either inhaled corticosteroids alone in a daily dose of up to 2,000 µg beclomethasone dipropionate/2,000 µg budesonide/1,000 µg FP or half the dose of the above inhaled corticosteroids in combination with second-line controller therapy such as with long-acting ß₂-agonists or leukotriene receptor antagonists. Patients were required to exhibit airway hyperresponsiveness to methacholine on bronchial challenge testing with a provocative dose of methacholine causing a 20% fall in FEV₁ (PC₂₀) of < 4.0 mg/mL.¹² Informed consent was obtained from all patients, and the Tayside Committee on Medical Research Ethics approved the study.

Study Design
The study design schematic is shown in Figure 1 . The study was conducted in a randomized, double-blind, double-dummy, crossover fashion. Patients were required to stop receiving their usual inhaled corticosteroids along with their second-line controller therapy for the duration of the study. Patients began receiving salmeterol (Serevent Accuhaler; GlaxoSmithKline; Uxbridge, UK), 50 µg one puff twice daily, and montelukast (Singulair; Merck Sharp & Dohme Ltd; Hoddesdon, UK), 10 mg once daily during the 2-week washout periods prior to each randomized treatment, in order to prevent dropouts after inhaled corticosteroid withdrawal. Patients were randomized to receive for 4 weeks either hydrofluoroalkane formulations of CIC (Alvesco; Altana Pharma AG; Konstanz, Germany), 200 µg ex-valve (160 µg ex-actuator) four puffs twice daily (8:00 AM and 8:00 PM), plus FP-placebo, four puffs twice daily (8:00 AM and 8:00 PM), or FP (Flixotide Evohaler; GlaxoSmithKline), 250 µg ex-valve (220 µg ex-actuator) four puffs twice daily (8:00 AM and 8:00 PM), plus CIC-placebo, four puffs twice daily (8:00 AM and 8:00 PM). Active and placebo devices for each drug were masked to make them identical in external physical appearance. Salmeterol and montelukast were withheld for 72 h prior to each baseline visit after each washout period, and CIC or FP was withheld for 12 h prior to each study visit. A compliance of at least 90% with study medication was required on a tick chart for data inclusion.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Study design schematic depicting the washout and randomized treatment periods, with study visits 0 (V0) to 4 (V4).

Spirometry: Spirometry was performed according to the American Thoracic Society criteria¹³ (SuperSpiro; Micro Medical Ltd; Rochester, UK).

Exhaled Nitric Oxide: Measurements were performed as previously described¹⁴ using an integrated device (LR2000 clinical real-time nitric oxide gas analyzer; Logan Research; Rochester, UK) with a flow rate of 250 mL/min and an accuracy of 2 parts per billion nitric oxide, with a response time of 2 s.

Methacholine Bronchial Challenge: Methacholine was administered using a standardized breath-actuated dosimeter (Mefar dosimeter; Markos-Mefar SpA; Bovezzo, Italy) at 5-min intervals in doubling cumulative concentrations from 0.03125 to 64.0 mg/mL until a 20% reduction in FEV₁ was recorded. Log-linear interpolation was performed using a computer-assisted program (Micro Medical Ltd) to calculate the PC₂₀ values.

Domiciliary Peak Expiratory Flow, Symptom Score, and Rescue Diary: Patients recorded morning and evening domiciliary peak expiratory flow using a peak flowmeter (Mini-Wright; Clement Clarke International Ltd; Harlow, UK) along with documentation of asthma symptom scores on a 4-point scale (0, no symptoms; 3, severe symptoms) and rescue inhaler use for the duration of the study.

Mini-Asthma Quality-of-Life Questionnaire: Patients completed the Mini-Asthma Quality-of-Life Questionnaire (MiniAQLQ),¹⁵ which consisted of four domains (symptoms, five items; activity limitation, four items; emotional function, three items; and environmental stimuli, three items), on each study visit.

Statistical Analysis
The study was powered at 80% in order to detect a 30% difference in plasma cortisol levels after hCRF stimulation (the primary systemic outcome variable) as a change from baseline, and a one-doubling-dilution difference in PC₂₀ (the primary efficacy outcome variable) as a change from baseline. All other outcomes were considered as secondary. For all comparisons, an overall analysis of variance was performed, followed by multiple-range testing, with the Bonferroni correction set at the 95% confidence interval (CI), in order to obviate multiple pairwise comparisons. The results of the multiple-range test are quoted as being either significant at p < 0.05 (two-tailed) or nonsignificant. To normalize the distribution, data for plasma cortisol levels, overnight 10-h urinary cortisol (OUC) levels, exhaled nitric oxide levels, and methacholine PC₂₀ were logarithmically transformed, and analyses were performed using a statistical software package (Statgraphics; STSC Software Publishing Group; Rockville, MD).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
Twenty patients were recruited into the study and randomized from the database based on previous recordings of bronchial hyperresponsiveness to methacholine, lung function, and inhaled corticosteroid therapy, in keeping with the presence of moderate, persistent asthma. Three patients had FEV₁ values < 60% predicted following the washout period, which precluded a methacholine challenge. Of the remaining 17 patients, 2 patients dropped out of the study due to an asthma exacerbation during the study (1 patient at each randomized treatment limb) and 1 patient dropped out due to personal reasons. Fourteen patients (9 men and 5 women), with a mean (± SEM) age of 47 ± 3 years, a mean FEV₁ of 2.44 ± 0.16 L (77 ± 4% predicted), a mean forced expiratory flow, midexpiratory phase (FEF_25–75) of 2.00 ± 0.16 L/s (52 ± 3% predicted), and a geometric mean methacholine PC₂₀ of 0.7 ± 0.2 mg/mL, completed the study per protocol. The mean beclomethasone dipropionate equivalent dose of inhaled corticosteroids was 829 ± 55 µg daily, which was composed of beclomethasone dipropionate (n = 7), budesonide (n = 1), and FP (n = 6). Seven patients were receiving second-line controller therapy with drugs such as formoterol (n = 2), salmeterol (n = 3), and montelukast (n = 2).

HPA Axis
Individual data for plasma cortisol levels before and after hCRF stimulation, as well as OUC levels are shown in Figures 2 , 3 , and 4 . Pretreatment (postwashout) baseline values and posttreatment values for plasma cortisol and OUC levels are shown in Tables 1and 2 . Baseline values after each washout period, prior to each randomized treatment, were not significantly different. Moreover, baseline values by sequence, irrespective of subsequent treatments, were not significantly different, indicating a lack of any carryover effects between randomized treatments. There was significant suppression (p < 0.05) of pre-hCRF administration cortisol levels, 30-min post-hCRF administration cortisol levels, and OUC levels, when comparing values before and after FP administration. Values for 60-min post-hCRF administration cortisol levels were not significantly different comparing pre-FP administration and post-FP administration levels. There was no significant suppression of any HPA axis outcomes when comparing values before and after CIC administration. There was a significantly lower mean value for OUC levels after FP administration than after CIC administration (geometric mean fold difference, 1.5; 95% CI, 1.1 to 2.0). There were also significantly more (p < 0.05) patients with low OUC levels of < 10 nmol per 10 h after FP administration (n = 7) than after CIC administration (n = 1). However, values for cortisol levels before and after hCRF administration were not significantly different when comparing values obtained after treatment with CIC and FP.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Individual values for basal pre-hCRF administration plasma cortisol levels, showing mean (SEM) pretreatment and posttreatment values coupled for each individual. A significant mean comparison for pretreatment vs posttreatment values is denoted by p < 0.05.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 3.. Individual values for 30-min post-hCRF administration plasma cortisol levels, showing mean (SEM) pretreatment and posttreatment values coupled for each individual. A significant mean comparison for pretreatment vs posttreatment values is denoted by p < 0.05.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 4.. Individual values for OUC levels, showing mean (SEM) pretreatment and posttreatment values coupled for each individual. A significant mean comparison for pretreatment vs posttreatment values is denoted by p < 0.05.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 5.. Individual values for methacholine PC20, showing mean (SEM) doubling dilution difference from baseline values coupled for each individual. Both treatments caused a significant doubling dilution difference (p < 0.05) in PC20 relative to pretreatment baseline values.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Our results showed that, in terms of systemic safety, treatment for 4 weeks with hydrofluoroalkane formulations of FP, 2,000 µg daily, but not CIC, 1,600 µg daily, produced significant HPA axis suppression relative to baseline values for both plasma and urinary cortisol. Furthermore, mean values for OUC levels were significantly lower after FP administration than after CIC administration. Indeed, when inspecting individual values for OUC levels, there were significantly more abnormally low values after FP administration than after CIC administration. For efficacy outcomes that were indicative of airway inflammation and bronchial hyperresponsiveness, therapy with both CIC and FP significantly improved exhaled nitric oxide levels and methacholine PC₂₀ values relative to baseline. For other airway outcomes, including spirometry, peak expiratory flow, symptoms, and MiniAQLQ score, neither treatment had any significant effect. Taken together, the present findings therefore suggest that CIC may confer a better therapeutic ratio than FP when used at higher doses.

In considering the relative HPA axis suppression, both drugs have almost complete hepatic first-pass inactivation for the swallowed fraction, such that systemic bioactivity would be determined by lung bioavailability. One could argue that the ex-actuator dose of CIC was 27% lower than that for FP, which could partly explain the greater systemic bioactivity seen with FP therapy. However, this simple calculation would not take into account the twofold higher respirable fraction with CIC than that with FP.¹ Another important factor is the amount of unbound, freely circulating drug,¹ with FP having 10-fold lower plasma protein binding than CIC (90% and 99%, respectively). This would explain the lack of any detectable HPA axis suppression with CIC doses up to 1,600 µg, as has been seen in previous studies.¹²³⁴

There was only modest suppression of the HPA axis with FP therapy in our study, particularly for the stimulated cortisol response to hCRF stimulation. This observation is perhaps not surprising in view of the presence of previous studies in the literature that had shown that the amount of HPA axis suppression is directly related to the degree of impairment of airway caliber.¹⁶¹⁷¹⁸ Thus, our patients who had moderately impaired airway caliber would be relatively protected from developing systemic adverse effects with high-dose FP therapy, due to the reduced bioavailability from the lung. It is therefore relevant to note that there was a fall in mean FEV₁ from the initial screening value while patients were receiving their usual inhaled corticosteroids (77% predicted) to the mean postwashout baseline value after switching to therapy with montelukast plus salmeterol (67% predicted) prior to starting each randomized treatment. In a previous study¹⁹ comparing healthy volunteers (mean FEV₁, 104% predicted) and patients with severe asthma who had impaired airway caliber (mean FEV₁, 47% predicted), who each received 2 weeks of therapy with FP, 2,000 µg daily, we found marked suppression in the healthy subjects but no suppression in the asthmatic subjects, for the hCRF-stimulated cortisol response.

It is difficult to be fully certain whether the observed changes will be clinically relevant in terms of dynamic HPA axis suppression, but, as one can see from the individual values in Figures 2, 3 , and 4, there is considerable interpatient variation in the propensity for the suppression of both the hCRF and OUC responses, so that in a given individual it is possible that the effects observed with FP therapy would be clinically relevant in the longer term. If one does not observe the presence of any systemic signal over a 4-week period, then it would be logical to assume that one would not see any effects over months or years, as steady-state blood levels would have been reached within the first week of treatment. By the same token, it would be unlikely that the systemic signal seen with FP administration would be any greater over longer periods of time. Moreover, we are not aware at present of any data demonstrating the development of tolerance to HPA axis suppression over time.

We do not think that the duration of therapy with FP for 4 weeks was too short to detect dynamic HPA axis suppression, as previous data with high-dose budesonide, 2,000 µg daily administered for 5 days, showed significant suppression of hCRF plasma cortisol levels in asthmatic patients with a mean FEV₁ of 89% predicted.²⁰ Another factor to take into consideration is the hydrofluoroalkane formulation of FP. It has previously been shown that the systemic bioavailability of the hydrofluoroalkane FP suspension formulation is significantly lower than that of the chlorofluorocarbon FP suspension formulation for the same nominal dose.²¹ Moreover, the degree of HPA axis suppression is significantly lower with the hydrofluoroalkane FP formulation than with the chlorofluorocarbon FP formulation.²²²³²⁴ Thus, although the nominal dose of hydrofluoroalkane FP was high at 2,000 µg, its lower systemic bioavailability would in part, along with reduced airway caliber, explain the lower-than-expected magnitude of adrenal suppression.

We thought that it was important to conduct a study whereby there was an inhaled corticosteroid-free washout period in order to properly assess the degree of HPA axis suppression in response to CIC or FP administration. Since our patients had moderate asthma, we thought that it was unethical and impractical, due to a potentially high dropout rate, to have patients stopping their therapy with inhaled corticosteroids for > 2 weeks. We thought that 2 weeks was a sufficient time to washout CIC and FP, particularly in view of previous data²⁵ showing that basal and hCRF-stimulated plasma cortisol levels returned to baseline values after 3 days of not receiving high-dose FP therapy.

The apparent disconnection between a significant improvement in bronchial hyperresponsiveness but not in lung function that we observed has been well-documented.²⁶ We found a similar improvement with both drugs for the doubling-dilution difference in methacholine bronchial hyperresponsiveness. In this respect, the glucocorticoid receptor-binding affinity of FP is higher than that of CIC,¹ although this may be offset by the higher respirable dose delivery of the hydrofluoroalkane solution formulation of CIC than that for the suspension formulation of FP. We believe that the 4-week duration of inhaled corticosteroid therapy in our study was adequate on the basis of previous data using direct bronchial challenges with either histamine or methacholine, which have shown no further change in bronchial hyperresponsiveness after 2 weeks, comparing 4 or 6 weeks of treatment.²⁷²⁸ However, it is possible that a further small change in methacholine bronchial hyperresponsiveness might have been seen after 6 months.

We used the combination of salmeterol plus montelukast during each washout period in order to prevent dropouts due to the withdrawal of therapy with inhaled corticosteroids. This was based on data from a previous proof-of-concept study²⁹ in patients with moderate, persistent asthma, which showed that the combination of salmeterol plus montelukast prevented a marked decline in lung function and methacholine hyperresponsiveness after the withdrawal of therapy with inhaled corticosteroids in patients with moderate, persistent asthma. Therapy with salmeterol plus montelukast was stopped for a 72-h period prior to each baseline measurement. We accept that there may have been a small degree of carryover for the effect on montelukast at each baseline measurement, although this would have been the same for each randomized treatment, as shown by the similar values for both pretreatment baselines. Moreover, we were confident that any effect of montelukast would have disappeared by the end of each 4-week randomized treatment block.

In summary, therapy with FP, 2,000 µg daily, but not with CIC, 1,600 µg daily, significantly suppressed HPA axis outcomes, with OUC levels being lower after FP administration than after CIC administration. Both drugs significantly improved efficacy outcomes in terms of exhaled nitric oxide levels and methacholine bronchial hyperresponsiveness. Taken together, the present results therefore suggest that CIC may confer a better therapeutic ratio than FP when used at higher doses.

	Footnotes

 
Abbreviations: CI = confidence interval; CIC = ciclesonide; FEF_25–75 = forced expiratory flow, midexpiratory phase; FP =fluticasone propionate; hCRF = human corticotropin-releasing factor; HPA = hypothalamic-pituitary-adrenal; Mini-AQLQ = Mini-Asthma Quality-of-Life Questionnaire; OUC = overnight 10-h urinary cortisol; PC₂₀ = provocative concentration of methacholine causing a 20% fall in FEV₁

This study was supported by an unrestricted educational grant from Aventis Pharmaceuticals. Dr. Lipworth has received support from Aventis Pharmaceuticals to attend educational meetings.

Received for publication March 16, 2004. Accepted for publication October 27, 2004.

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